Fetal alcohol syndrome includes a series of teratologic malformations resulting in deficits in the immune and central nervous systems (CNS), but the molecular signals which induce these deficits are largely unknown. There are important interactions between neurons and glial cells during development in the CNS. These interactions include the removal of excessive neurons and axons which are produced during development. The cells involved in this tissue remodelling include two types of glia: microglia (brain macrophages) and astrocytes, which produce and respond to cytokines. Ethanol alters neuronal cell proliferation and differentiation, glial function, and norma cell death in the developing CNS resulting in an overall decrease in neuronal cell number. Our general hypothesis is that ethanol-induced injury in the CNS is mediated through the action of microglia/macrophages and astrocytes which produce tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO), two intercellular messengers which mediate cell death. The specific aims are: i) to determine the patterns of expression of TNF-alpha and NO in the developing cortex, under normal conditions and following ethanol treatment; and ii) to determine the time course and magnitude of cell death in cerebral cortex from control and ethanol-treated mice and relate cell death to cytokine and NO production. Cell death may be classified into two general categories: apoptosis (nuclear cell death) and necrosis (cytoplasmic cell death). We will study the effects of ethanol on apoptosis in the neuroepithelium of the developing cerebral and cerebellar cortex. We anticipate that our studies will show that ethanol administration increases TNF-alpha and NO expression that is associated with cell death in the developing cortex. In addition to the relevance of these studies to fetal alcohol syndrome, microglial expression of molecules which cause neuron death is relevant to the mechanisms of the AIDS-dementia complex. In fact, there is evidence that ethanol consumption affects cells of the immune system, resulting in immunosuppression and enhanced viral proliferation during AIDS infection in both mice and humans.